Regulation of Ras Localization by Acylation Enables a Mode of Intracellular Signal Propagation

Sci. Signal., 21 September 2010
Vol. 3, Issue 140, p. ra68
DOI: 10.1126/scisignal.20001370

Regulation of Ras Localization by Acylation Enables a Mode of Intracellular Signal Propagation

  1. Anna Lorentzen1,2,
  2. Ali Kinkhabwala3,
  3. Oliver Rocks1,4,
  4. Nachiket Vartak3, and
  5. Philippe I. H. Bastiaens1,3,5,*
  1. 1European Molecular Biology Laboratory, Meyerhofstrasse 1, 69117 Heidelberg, Germany.
  2. 2Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK.
  3. 3Department of Systemic Cell Biology, Max Planck Institute of Molecular Physiology, Otto-Hahn-Strasse 11, 44227 Dortmund, Germany.
  4. 4Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, Ontario, Canada M5G 1X5.
  5. 5Technische Universität Dortmund, Fachbereich Chemie, 44227 Dortmund, Germany.
  1. *To whom correspondence should be addressed. E-mail: philippe.bastiaens{at}mpi-dortmund.mpg.de

Abstract

Growth factor stimulation generates transient H-Ras activity at the plasma membrane but sustained activity at the Golgi. Two overlapping regulatory networks control compartmentalized H-Ras activity: the guanosine diphosphate–guanosine triphosphate cycle and the acylation cycle, which constitutively traffics Ras isoforms that can be palmitoylated between intracellular membrane compartments. Quantitative imaging of H-Ras activity after decoupling of these networks revealed regulation of H-Ras activity at the plasma membrane but not at the Golgi. Nevertheless, upon stimulation with epidermal growth factor, Ras activity at the Golgi displayed a pulse-like profile similar to that at the plasma membrane but also remained high after the initial stimulus. A compartmental model that included the acylation cycle and H-Ras regulation at the plasma membrane accounted for the pulse-like profile of H-Ras activity at the Golgi but implied that sustained H-Ras activity at the Golgi required H-Ras activation at an additional compartment, which we experimentally determined to be the endoplasmic reticulum. Thus, in addition to maintaining the localization of Ras, the acylation cycle underlies a previously unknown form of signal propagation similar to radio transmission in its generation of a constitutive Ras “carrier wave” that transmits Ras activity between subcellular compartments.

Citation:

A. Lorentzen, A. Kinkhabwala, O. Rocks, N. Vartak, and P. I. Bastiaens, Regulation of Ras Localization by Acylation Enables a Mode of Intracellular Signal Propagation. Sci. Signal. 3, ra68 (2010).

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